Abstract Multiple sclerosis (MS) is a potentially progressive, autoimmune neurological disorder of the central nervous system (CNS) white matter presumably mediated by autoreactive CD4+ T cells. The disease is a consequence of both genetic predisposition and environmental triggers. Recent genome-wide association studies (GWAS) have identified over 100 genetic variants associated with increased risk of developing MS. Many of these variants fall in a limited number of signaling cascades primarily associated with immune responses and cytokine signaling, which suggests they are key biological nodes where genetic and environmental cues interact to predispose an individual towards autoimmunity, prior to the onset of disease. However, the functional mechanisms by which these variants impact immune responses, and ultimately lead to the development of MS, are largely unknown. Understanding the disease risk state mediated by these variants would allow us to determine both the pathogenesis of MS and also identify individuals ? irrespective of genetic load ? who exhibit it and are consequently at risk. Thus, uncovering this state has implications both for early diagnosis and the development of biomarkers and new therapeutic agents. NF?B is a master regulator of both innate and adaptive immunity, and is critical for activation, proliferation, differentiation, and cytokine production in multiple immune cell types, including the CD4+ T cells critical to MS pathogenesis. GWAS studies have identified NF?B as a central pathway in susceptibility to multiple autoimmune conditions including MS, and several strands of evidence support its causal role: MS patients exhibit higher NF?B signaling than controls; many GWAS risk variants affect NF?B signaling; and several MS disease-modifying agents inhibit this pathway. It is therefore an excellent model system to explore genetically mediated alterations in signaling cascades associated with disease. Here, we propose a systematic dissection of how alterations in NF?B signaling lead to altered gene regulatory programs and CD4+ T cell function, as an archetype of a disease-causing pathway inducing a risk state. To do so we will (i) establish how MS genetic variants alter stimulus-dependent NF?B signaling in CD4+ T cells alter gene regulation; and (ii) determine how MS risk variants in NFkB binding sites affect regulation of target genes. We will use an innovative, integrated genome-wide genomic approach simultaneously assessing NF?B signaling, its binding to and concomitant activation of cis-regulatory regions and resulting gene expression. Thus we will develop an experimental paradigm to comprehensively examine how risk variants affecting gene regulation lead to autoimmune disease risk. These studies represent significant innovation, as they take an integrative, unbiased approach to the problem of understanding how changes to NF?B-mediated signaling result in alterations to gene regulatory programs and subsequent differences CD4+ T cell phenotype.